Flavonoids with Inhibitory Effects on NLRP3 Inflammasome Activation from Millettia velutina
2020
Ma, Xu | Zhao, Min | Tang, Ming-Hai | Xue, Lin-Lin | Zhang, Rui-Jia | Liu, Ling | Ni, Heng-Fan | Cai, Xiao-Ying | Kuang, Shuang | Hong, Feng | Wang, Lun | Chen, Kai | Tang, Huan | Li, Yan | Peng, Ai-Hua | Yang, Jian-Hong | Pei, He-Ying | Ye, Hao-Yu | Chen, Li-Juan
Eight new flavonoids, including two β-hydroxy/methoxychalcones, velutones A and B (1 and 2), two 1,3-diarylpropan-1-ols, velutols C and D (3 and 4), a dihydroxychalcone, velutone E (5), a chalcone, velutone F (6), a furanoflavanone, velutone G (7), and a furanoflavonol, velutone H (8), and 14 known compounds were isolated from Millettia velutina. Their structures were determined by high-resolution electrospray ionisation mass spectrometry (HR-ESIMS) and spectroscopic data analyses and time-dependent density functional theory electronic circular dichroism (TD-DFT–ECD) calculations. Among the isolated constituents, compound 6 exhibited the most potent inhibitory effect (IC₅₀: 1.3 μM) against nigericin-induced IL-1β release in THP-1 cells. The initial mechanism of action study revealed that compound 6 suppressed NLRP3 inflammasome activation via blocking ASC oligomerization without affecting the priming step, which subsequently inhibited caspase-1 activation and IL-1β secretion. Most importantly, compound 6 exerted potent protective effects in the LPS-induced septic shock mice model by improving the survival rate of mice and suppressing serum IL-1β release. These results demonstrated that compound 6 had the potential to be developed as a broad-spectrum NLRP3 inflammasome inhibitor for the treatment of NLRP3-related disease.
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